Lurasidone
Encyclopedia
Lurasidone is an atypical antipsychotic
developed by Dainippon Sumitomo Pharma
. It was approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia
on October 28, 2010 and is currently pending approval for the treatment of bipolar disorder
in the United States
.
CYP3A4
. This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole
or grapefruit juice
, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin
or St. John's wort can reduce plasma levels and consequently the effects of the drug.
(Ki = 0.47 nM), 5-HT7
(Ki = 0.495 nM), and α2C-adrenergic
(Ki = 10.8 nM) receptor antagonist
, and 5-HT1A
(Ki = 6.75 nM) receptor agonist
. It has only weak or negligible actions at the 5-HT2C
, α1-adrenergic
, H1
, and mACh
receptors.
s, delusion
s) and negative (e.g., apathy
, emotional withdrawal
) symptom
s of schizophrenia without inducing extrapyramidal side effects except for akathisia
, despite its potent D2 antagonistic actions.
Lurasidone may be useful for treating cognitive
and memory
deficit
s seen in schizophrenia for several reasons: 1) unlike many other antipsychotics, lurasidone does not block the muscarinic acetylcholine receptors, an action well-known to impair learning
and memory
; 2) lurasidone has prominent activity at 5-HT1A, 5-HT2A, 5-HT7, and α2C-adrenergic receptors, all of which have been implicated in enhancement of cognitive function if modulated properly; 3) due to its low liability for extrapyramidal symptoms, lurasidone is unlikely to require coadministration of anticholinergic
s, which impair cognition in their own right. In animal studies, lurasidone was found to be superior to all of the other antipsychotics examined in reversing dizocilpine
-induced learning
and memory impairment, including risperidone
, olanzapine
, quetiapine
, clozapine
, aripiprazole
, and haloperidol
.
profile, with low propensity for extrapyramidal symptoms, QTc interval
changes, and weight
, lipid
, and glucose
-related adverse effects. Side effects reported in at least 5% of subjects and at least twice the frequency of placebo
include akathisia
(17.6% vs 3.1% placebo), somnolence
(11.7% vs 5.5%), parkinsonism
(6.8% vs 0%), and weight gain
(5.1% vs 2.4%).
Severe but infrequent side effects include neuroleptic malignant syndrome
and tardive dyskinesia
. As with other atypical neuroleptics, lurasidone should not be used in elderly patients because it puts them at an increased risk for a stroke
or transient ischemic attack
.
Atypical antipsychotic
The atypical antipsychotics are a group of antipsychotic tranquilizing drugs used to treat psychiatric conditions. Some atypical antipsychotics are FDA approved for use in the treatment of schizophrenia...
developed by Dainippon Sumitomo Pharma
Dainippon Sumitomo Pharma
is a pharmaceutical company based in Japan.The original Dainippon Pharmaceuticals was established in 1885 by Nagayo Sensai, a graduate of Tekijuku – the first private medical school in Japan established by Ogata Kōan. It was set up as a wholly private company invested by a number of people in...
. It was approved by the U.S. Food and Drug Administration (FDA) for treatment of schizophrenia
Schizophrenia
Schizophrenia is a mental disorder characterized by a disintegration of thought processes and of emotional responsiveness. It most commonly manifests itself as auditory hallucinations, paranoid or bizarre delusions, or disorganized speech and thinking, and it is accompanied by significant social...
on October 28, 2010 and is currently pending approval for the treatment of bipolar disorder
Bipolar disorder
Bipolar disorder or bipolar affective disorder, historically known as manic–depressive disorder, is a psychiatric diagnosis that describes a category of mood disorders defined by the presence of one or more episodes of abnormally elevated energy levels, cognition, and mood with or without one or...
in the United States
United States
The United States of America is a federal constitutional republic comprising fifty states and a federal district...
.
Pharmacokinetics and interactions
Lurasidone is metabolized in the liver via the enzymeEnzyme
Enzymes are proteins that catalyze chemical reactions. In enzymatic reactions, the molecules at the beginning of the process, called substrates, are converted into different molecules, called products. Almost all chemical reactions in a biological cell need enzymes in order to occur at rates...
CYP3A4
CYP3A4
Cytochrome P450 3A4 , a member of the cytochrome P450 mixed-function oxidase system, is one of the most important enzymes involved in the metabolism of xenobiotics in the body. CYP3A4 is involved in the oxidation of the largest range of substrates of all the CYPs. As a result, CYP3A4 is present in...
. This means that its plasma concentrations may be increased when combined with CYP3A4 inhibitors like ketoconazole
Ketoconazole
Ketoconazole is a synthetic antifungal drug used to prevent and treat fungal skin infections, especially in immunocompromised patients such as those with AIDS or those on chemotherapy. Ketoconazole is sold commercially as an anti-dandruff shampoo, topical cream, and oral tablet.Ketoconazole is...
or grapefruit juice
Grapefruit juice
Grapefruit juice is the fruit juice from grapefruits. It is rich in Vitamin C and ranges from sweet-tart to very sour. It is considered by some cultures to be a mystical tonic which promotes health and vigor. Certain civilizations have had holy men who live on Grapefruit juice alone...
, possibly leading to more side effects. Co-administration of CYP3A4 inducers like rifampicin
Rifampicin
Rifampicin or rifampin is a bactericidal antibiotic drug of the rifamycin group. It is a semisynthetic compound derived from Amycolatopsis rifamycinica ...
or St. John's wort can reduce plasma levels and consequently the effects of the drug.
Pharmacodynamics
Lurasidone acts as a D2 (Ki = 0.994 nM), 5-HT2A5-HT2A receptor
The mammalian 5-HT2A receptor is a subtype of the 5-HT2 receptor that belongs to the serotonin receptor family and is a G protein-coupled receptor . This is the main excitatory receptor subtype among the GPCRs for serotonin , although 5-HT2A may also have an inhibitory effect on certain areas such...
(Ki = 0.47 nM), 5-HT7
5-HT7 receptor
The 5-HT7 receptor is a member of the GPCR superfamily of cell surface receptors and is activated by the neurotransmitter serotonin The 5-HT7 receptor is coupled to Gs and is expressed in a variety of human tissues, particularly in the brain, the gastrointestinal tract, and in various...
(Ki = 0.495 nM), and α2C-adrenergic
Alpha-2C adrenergic receptor
The alpha-2C adrenergic receptor , also known as ADRA2C, is an alpha-2 adrenergic receptor, and also denotes the human gene encoding it.-Agonists:* -3-Nitrobiphenyline -Antagonists:...
(Ki = 10.8 nM) receptor antagonist
Receptor antagonist
A receptor antagonist is a type of receptor ligand or drug that does not provoke a biological response itself upon binding to a receptor, but blocks or dampens agonist-mediated responses...
, and 5-HT1A
5-HT1A receptor
The 5-HT1A receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gi/Go and mediates inhibitory neurotransmission...
(Ki = 6.75 nM) receptor agonist
Agonist
An agonist is a chemical that binds to a receptor of a cell and triggers a response by that cell. Agonists often mimic the action of a naturally occurring substance...
. It has only weak or negligible actions at the 5-HT2C
5-HT2C receptor
The 5-HT2C receptor is a subtype of 5-HT receptor that binds the endogenous neurotransmitter serotonin . It is a G protein-coupled receptor that is coupled to Gq/G11 and mediates excitatory neurotransmission. HTR2C denotes the human gene encoding for the receptor, that in humans is located at the...
, α1-adrenergic
Alpha-1 adrenergic receptor
The alpha-1 adrenergic receptor is a G protein-coupled receptor associated with the Gq heterotrimeric G-protein. It consists of three highly homologous subtypes, including α1A-, α1B-, and α1D-adrenergic...
, H1
H1 receptor
The H1 receptor is a histamine receptor belonging to the family of Rhodopsin like G-protein-coupled receptors. This receptor, which is activated by the biogenic amine histamine, is expressed throughout the body, to be specific, in smooth muscles, on vascular endothelial cells, in the heart, and in...
, and mACh
Muscarinic acetylcholine receptor
Muscarinic receptors, or mAChRs, are acetylcholine receptors that form G protein-coupled in the plasma membranes of certain neurons and other cells...
receptors.
Uses
In clinical studies, lurasidone alleviates both positive (e.g., hallucinationHallucination
A hallucination, in the broadest sense of the word, is a perception in the absence of a stimulus. In a stricter sense, hallucinations are defined as perceptions in a conscious and awake state in the absence of external stimuli which have qualities of real perception, in that they are vivid,...
s, delusion
Delusion
A delusion is a false belief held with absolute conviction despite superior evidence. Unlike hallucinations, delusions are always pathological...
s) and negative (e.g., apathy
Apathy
Apathy is a state of indifference, or the suppression of emotions such as concern, excitement, motivation and passion. An apathetic individual has an absence of interest in or concern about emotional, social, spiritual, philosophical or physical life.They may lack a sense of purpose or meaning in...
, emotional withdrawal
Blunted affect
Blunted affect is the scientific term describing a lack of emotional reactivity on the part of an individual. It is manifest as a failure to express feelings either verbally or non-verbally, even when talking about issues that would normally be expected to engage the emotions...
) symptom
Symptom
A symptom is a departure from normal function or feeling which is noticed by a patient, indicating the presence of disease or abnormality...
s of schizophrenia without inducing extrapyramidal side effects except for akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
, despite its potent D2 antagonistic actions.
Lurasidone may be useful for treating cognitive
Cognition
In science, cognition refers to mental processes. These processes include attention, remembering, producing and understanding language, solving problems, and making decisions. Cognition is studied in various disciplines such as psychology, philosophy, linguistics, and computer science...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
deficit
Cognitive deficit
Cognitive deficit, also known as cognitive impairment is an inclusive term to describe any characteristic that acts as a barrier to cognitive performance...
s seen in schizophrenia for several reasons: 1) unlike many other antipsychotics, lurasidone does not block the muscarinic acetylcholine receptors, an action well-known to impair learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory
Memory
In psychology, memory is an organism's ability to store, retain, and recall information and experiences. Traditional studies of memory began in the fields of philosophy, including techniques of artificially enhancing memory....
; 2) lurasidone has prominent activity at 5-HT1A, 5-HT2A, 5-HT7, and α2C-adrenergic receptors, all of which have been implicated in enhancement of cognitive function if modulated properly; 3) due to its low liability for extrapyramidal symptoms, lurasidone is unlikely to require coadministration of anticholinergic
Anticholinergic
An anticholinergic agent is a substance that blocks the neurotransmitter acetylcholine in the central and the peripheral nervous system. An example of an anticholinergic is dicycloverine, and the classic example is atropine....
s, which impair cognition in their own right. In animal studies, lurasidone was found to be superior to all of the other antipsychotics examined in reversing dizocilpine
Dizocilpine
Dizocilpine , also known as MK-801, is a non-competitive antagonist of the N-methyl-d-aspartate receptor, a glutamate receptor. Glutamate is the brain's primary excitatory neurotransmitter...
-induced learning
Learning
Learning is acquiring new or modifying existing knowledge, behaviors, skills, values, or preferences and may involve synthesizing different types of information. The ability to learn is possessed by humans, animals and some machines. Progress over time tends to follow learning curves.Human learning...
and memory impairment, including risperidone
Risperidone
Risperidone is a second generation or atypical antipsychotic, sold under the trade name . It is used to treat schizophrenia , schizoaffective disorder, the mixed and manic states associated with bipolar disorder, and irritability in people with autism...
, olanzapine
Olanzapine
Olanzapine is an atypical antipsychotic, approved by the FDA for the treatment of schizophrenia and bipolar disorder...
, quetiapine
Quetiapine
Quetiapine , is an atypical antipsychotic approved for the treatment of schizophrenia, and bipolar disorder....
, clozapine
Clozapine
Clozapine is an antipsychotic medication used in the treatment of schizophrenia, and is also used off-label in the treatment of bipolar disorder. Wyatt. R and Chew...
, aripiprazole
Aripiprazole
Aripiprazole is an atypical antipsychotic and antidepressant used in the treatment of schizophrenia, bipolar disorder, and clinical depression...
, and haloperidol
Haloperidol
Haloperidol is a typical antipsychotic. It is in the butyrophenone class of antipsychotic medications and has pharmacological effects similar to the phenothiazines....
.
Side effects
Side effects are generally similar to other antipsychotics. The drug has a relatively well-tolerated side effectSide effect
In medicine, a side effect is an effect, whether therapeutic or adverse, that is secondary to the one intended; although the term is predominantly employed to describe adverse effects, it can also apply to beneficial, but unintended, consequences of the use of a drug.Occasionally, drugs are...
profile, with low propensity for extrapyramidal symptoms, QTc interval
QT interval
In cardiology, the QT interval is a measure of the time between the start of the Q wave and the end of the T wave in the heart's electrical cycle. In general, the QT interval represents electrical depolarization and repolarization of the left and right ventricles...
changes, and weight
Weight
In science and engineering, the weight of an object is the force on the object due to gravity. Its magnitude , often denoted by an italic letter W, is the product of the mass m of the object and the magnitude of the local gravitational acceleration g; thus:...
, lipid
Lipid
Lipids constitute a broad group of naturally occurring molecules that include fats, waxes, sterols, fat-soluble vitamins , monoglycerides, diglycerides, triglycerides, phospholipids, and others...
, and glucose
Glucose
Glucose is a simple sugar and an important carbohydrate in biology. Cells use it as the primary source of energy and a metabolic intermediate...
-related adverse effects. Side effects reported in at least 5% of subjects and at least twice the frequency of placebo
Placebo
A placebo is a simulated or otherwise medically ineffectual treatment for a disease or other medical condition intended to deceive the recipient...
include akathisia
Akathisia
Akathisia, or acathisia, is a syndrome characterized by unpleasant sensations of inner restlessness that manifests itself with an inability to sit still or remain motionless...
(17.6% vs 3.1% placebo), somnolence
Somnolence
Somnolence is a state of near-sleep, a strong desire for sleep, or sleeping for unusually long periods . It has two distinct meanings, referring both to the usual state preceding falling asleep, and the chronic condition referring to being in that state independent of a circadian rhythm...
(11.7% vs 5.5%), parkinsonism
Parkinsonism
Parkinsonism is a neurological syndrome characterized by tremor, hypokinesia, rigidity, and postural instability. The underlying causes of parkinsonism are numerous, and diagnosis can be complex...
(6.8% vs 0%), and weight gain
Weight gain
Weight gain is an increase in body weight. This can be either an increase in muscle mass, fat deposits, or excess fluids such as water.-Description:...
(5.1% vs 2.4%).
Severe but infrequent side effects include neuroleptic malignant syndrome
Neuroleptic malignant syndrome
Neuroleptic malignant syndrome is a life- threatening neurological disorder most often caused by an adverse reaction to neuroleptic or antipsychotic drugs...
and tardive dyskinesia
Tardive dyskinesia
Tardive dyskinesia is a difficult-to-treat form of dyskinesia that can be tardive...
. As with other atypical neuroleptics, lurasidone should not be used in elderly patients because it puts them at an increased risk for a stroke
Stroke
A stroke, previously known medically as a cerebrovascular accident , is the rapidly developing loss of brain function due to disturbance in the blood supply to the brain. This can be due to ischemia caused by blockage , or a hemorrhage...
or transient ischemic attack
Transient ischemic attack
A transient ischemic attack is a transient episode of neurologic dysfunction caused by ischemia – either focal brain, spinal cord or retinal – without acute infarction...
.